2P-353 : Aglycosylated IgG antibody Fc variants engineered for FcγRIIIa engagement and NK cell mediated tumor cell killing

Anti-tumor monoclonal antibodies exert clinical efficacy through a variety of mechanism of action. Among them, NK cell mediated ADCC has been considered the most critical tumor cell clearance mechanism in using anti-tumor monoclonal antibodies in the clinic. In spite of advantages aglycosylated antibody which allows simple bacterial production and bypasses glycan heterogeneity issue, aglycosylated antibody Fc has highly dynamic upper CH2 region and cannot bind to Fcγ RIII which is critical for the NK cell activation and cytotoxicity of tumor cells. For high FcγRIIIa binding and enhanced NK cell mediated tumor cell killing, we have constructed a large size full length IgG antibody Fc variant library and displayed using the covalent full-length IgG bacterial display system. By multiple rounds of high throughput flow cytometry screening, engineered Fc variants exhibiting remarkably improved FcγRIIIa binding affinity have been successfully isolated. Novel biophysical properties of the engineered FcγRIIIa binding aglycosylated full length IgG Fc variant have been characterized in vitro and the clinical utilities will be discussed.